Role of Hypotaurine in Protection against UVA-Induced Damage in Keratinocytes.

Photoageing and skin cancer are major causes of morbidity and are a high cost to society. Interest in the development of photoprotective agents for inclusion in topical cosmetic and sunscreen products is profound. Recently, amino acids with a sulfinic group, notably hypotaurine, have been included as ingredients in cosmetic preparations. However, the mechanism of action of hypotaurine as a possible anti-aging agent is unknown, despite its use as a free radical scavenger. To address this issue, we investigated hypotaurine uptake in a human keratinocyte model and examined its effect on UVR-induced cytotoxicity. Hypotaurine was taken up by keratinocytes in a time- and concentration-dependent manner, with levels remaining significantly above baseline 48 h after washout. A cytoprotective effect of pre-incubation with 2.5-5 mMhypotaurine was shown as indicated by increased cell viability when keratinocytes were irradiated with UVA at 5 or 10 Jcm-2 , with the level of hypotaurine also significantly reduced. These findings indicate a potential cytoprotective effect of hypotaurine against the deleterious effects of UVA irradiation. This provides support for further studies to evaluate the potential photoprotective benefits of hypotaurine supplementation of topical cosmetic and sunscreen products.

The Effect of Drug Pre-treatment on Taurine Transport at the Inner Blood-Retinal Barrier Under Variable Conditions.

Taurine is essential for the development and function of the central nervous system, retina, and cardiovascular system. It is a naturally occurring amino acid, abundantly found in the retina. It has been shown to exhibit antioxidant, neuroprotective, and osmoregulatory functions in the retina. We used conditionally immortalized rat retinal capillary endothelial cells (TR-iBRB), in vitro, to investigate the effects of oxidative stress, high glucose (HG) and hypertonic conditions on taurine transport. TR-iBRB cells pre-treated with tumor necrosis factor alpha (TNF-α) showed a significant increase in [3H]taurine uptake rate, which, however, decreased when treated with taurine (50 mM). Addition of paeonol and propranolol to TNF-α pre-treated cells had no significant effect on [3H]taurine uptake, but the addition of 10 mM taurine caused a reduction. The uptake rate decreased under HG conditions, in contrast to that under hypertonic conditions. [3H]Taurine uptake increased with pre-incubation time. Additionally, uptake of [3H]taurine and mRNA expression of taurine transporter (TauT) decreased significantly under hypertonic and HG conditions, following pre-incubation with 10 mM taurine, 1 mM paeonol, and 0.1 mM propranolol. [3H]Taurine uptake was significantly inhibited in the presence of taurine transporters such as taurine and ß-alanine. Results indicate that oxidative stress and hypertonic conditions increased taurine uptake in iBRB cell lines, whereas HG conditions reduced the uptake rate. Taurine may be useful in stabilizing the microenvironment in cells affected by oxidative stress as well as hypertonic and HG conditions. Moreover, taurine may play a key role in maintaining taurine concentrations in the taurine transporter system of retinal cells.

Biomarkers of oxidative stress, inflammation, and vascular dysfunction in inherited cystathionine ß-synthase deficient homocystinuria and the impact of taurine treatment in a phase 1/2 human clinical trial.

STUDY OBJECTIVE: A phase 1/2 clinical trial was performed in individuals with cystathionine ß synthase (CBS) deficient homocystinuria with aims to: (a) assess pharmacokinetics and safety of taurine therapy, (b) evaluate oxidative stress, inflammation, and vascular function in CBS deficiency, and (c) evaluate the impact of short-term taurine treatment. METHODS: Individuals with pyridoxine-nonresponsive CBS deficiency with homocysteine >50 µM, without inflammatory disorder or on antioxidant therapy were enrolled. Biomarkers of oxidative stress and inflammation, endothelial function (brachial artery flow-mediated dilation [FMD]), and disease-related metabolites obtained at baseline were compared to normal values. While maintaining current treatment, patients were treated with 75 mg/kg taurine twice daily, and treatment response assessed after 4 hours and 4 days. RESULTS: Fourteen patients (8-35 years; 8 males, 6 females) were enrolled with baseline homocysteine levels 161 ± 67 µM. The study found high-dose taurine to be safe when excluding preexisting hypertriglyceridemia. Taurine pharmacokinetics showed a rapid peak level returning to near normal levels at 12 hours, but had slow accumulation and elevated predosing levels after 4 days of treatment. Only a single parameter of oxidative stress, 2,3-dinor-8-isoprostaglandin-F2α, was elevated at baseline, with no elevated inflammatory parameters, and no change in FMD values overall. Taurine had no effect on any of these parameters. However, the effect of taurine was strongly related to pretreatment FMD values; and taurine significantly improved FMD in the subset of individuals with pretreatment FMD values <10% and in individuals with homocysteine levels >125 µM, pertinent to endothelial function. CONCLUSION: Taurine improves endothelial function in CBS-deficient homocystinuria in patients with preexisting reduced function.

Pharmacokinetic study and evaluation of the safety of taurolidine for dogs with osteosarcoma.

BACKGROUND: Osteosarcoma in dogs and humans share many similarities and the dog has been described as an excellent model to study this disease. The median survival in dogs has not improved in the last 25 years. Taurolidine has been shown to be cytotoxic to canine and human osteosarcoma in vitro. The goals of this study were to determine the pharmacokinetics and safety of taurolidine in healthy dogs and the safety of taurolidine in combination with doxorubicin or carboplatin in dogs with osteosarcoma. METHODS: Two percent taurolidine was infused into six healthy dogs (150 mg/kg) over a period of two hours and blood samples were taken periodically. One dog received taurolidine with polyvinylpyrrolidone (PVP) as its carrier and later received PVP-free taurolidine as did all other dogs in this study. Serum taurolidine concentrations were determined using high-performance liquid chromatography (HPLC) online coupled to ESI-MS/MS in the multiple reaction monitoring mode. Subsequently, the same dose of taurolidine was infused to seven dogs with osteosarcoma also treated with doxorubicin or carboplatin. RESULTS: Taurolidine infusion was safe in 6 healthy dogs and there were no significant side effects. Maximum taurolidine serum concentrations ranged between 229 to 646 µM. The dog that received taurolidine with PVP had an immediate allergic reaction but recovered fully after the infusion was stopped. Three additional dogs with osteosarcoma received doxorubicin and taurolidine without PVP. Toxicities included dilated cardiomyopathy, protein-losing nephropathy, renal insufficiency and vasculopathy at the injection site. One dog was switched to carboplatin instead of doxorubicin and an additional 4 dogs with osteosarcoma received taurolidine-carboplatin combination. One incidence of ototoxicity occurred with the taurolidine- carboplatin combination. Bone marrow and gastro-intestinal toxicity did not appear increased with taurolidine over doxorubicin or carboplatin alone. CONCLUSIONS: Taurolidine did not substantially exacerbate bone marrow or gastro-intestinal toxicity however, it is possible that taurolidine increased other toxicities of doxorubicin and carboplatin. Administering taurolidine in combination with 30 mg/m2 doxorubicin in dogs is not recommended but taurolidine in combination with carboplatin (300 mg/m2) appears safe.

Cigarette smoking predicts differential benefit from naltrexone for alcohol dependence.

BACKGROUND: Identifying factors that modify responsiveness to pharmacotherapies for alcohol dependence is important for treatment planning. Cigarette smoking predicts more severe alcohol dependence and poorer treatment response in general. Nevertheless, there is limited research on cigarette smoking as a potential predictor of differential response to pharmacological treatment of alcoholism. METHODS: We examined the association between cigarette smoking and drinking outcomes in the COMBINE (Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence) study, a randomized, double-blind placebo-controlled 16-week trial comparing combinations of medications (i.e., acamprosate and naltrexone) and behavioral interventions (i.e., medical management, combined behavioral therapy) in 1383 alcohol-dependent individuals. RESULTS: Smokers (i.e., more than one half the sample) significantly differed from nonsmokers on several demographic and drinking-related variables at baseline and generally had poorer treatment outcomes than nonsmokers. However, smokers who received naltrexone had better drinking outcomes than smokers who received placebo, whereas alcohol use among nonsmokers did not vary by naltrexone assignment. This pattern of findings occurred independent of whether patients received combined behavioral intervention or medical management and remained after controlling for alcoholism typology and baseline demographic differences. Approximately 9% of smokers quit smoking, and an additional 10% reduced their cigarette intake during treatment. Reductions in smoking did not vary by treatment assignment. CONCLUSIONS: These results suggest that naltrexone might be particularly beneficial for improving alcohol use outcomes in alcohol-dependent smokers.

Reversed-phase liquid chromatographic determination of tramiprosate in rat plasma using evaporative light scattering detector.

A simple and reliable method was developed for determining blood concentrations of tramiprosate using reversed-phase HPLC with evaporative light scattering detection. The optimum evaporator and nebulizer temperatures for ELSD were set at 90 and 60°C respectively. The method was linear for a concentration range of 10-1000 µg/mL when 0.3 mL blood was used. The intra-assay precision ranged from 1.84 to 5.24%, and the coefficient of variation (CV) for a quality control sample at 10 µg/mL was 5.24% with a bias of -9.50% from the target value. The inter-assay precision ranged from 2.58 to 5.96%, and the CV for a quality control sample at 10 µg/mL was 5.96% with a bias of -7.50% from the target value. The method described here is suitable for management of tramiprosate in Alzheimer disease therapy.

The blood-brain barrier transport and cerebral distribution of guanidinoacetate in rats: involvement of creatine and taurine transporters.

Although the cerebral accumulation of guanidinoacetate (GAA) contributes to neurological complications in S-adenosylmethionine:guanidinoacetate N-methyltransferase (GAMT) deficiency, how GAA is abnormally distributed in the brain remains unknown. The purpose of this study was to investigate the transport of GAA across the blood-brain barrier (BBB) and in brain parenchymal cells in rats. [(14)C]GAA microinjected into the rat cerebrum was not eliminated from the brain, implying the negligible contribution of GAA efflux transport across the BBB. In contrast, in vivo analysis and an uptake study by TR-BBB cells, a rat in vitro BBB model, revealed that GAA was transported from the circulating blood across the BBB most likely via a creatine transporter (CRT). Although CRT at the BBB is almost saturated by endogenous creatine under physiological conditions, the creatine level in the blood significantly decreases in GAMT deficiency. This might lead to the increase of CRT-mediated blood-to-brain transport of GAA at the BBB. Furthermore, [(14)C]GAA was taken up by brain parenchymal cells in a concentrative manner most likely via taurine transporter and CRT. These characteristics of GAA transport across the BBB and in the brain parenchymal cells could be the key factors that facilitate GAA accumulation in the brains of patients with GAMT deficiency.

Tolerability of inhaled N-chlorotaurine in the pig model.

BACKGROUND: N-chlorotaurine, a long-lived oxidant produced by human leukocytes, can be applied in human medicine as an endogenous antiseptic. Its antimicrobial activity can be enhanced by ammonium chloride. This study was designed to evaluate the tolerability of inhaled N-chlorotaurine (NCT) in the pig model. METHODS: Anesthetized pigs inhaled test solutions of 1% (55 mM) NCT (n = 7), 5% NCT (n = 6), or 1% NCT plus 1% ammonium chloride (NH4Cl) (n = 6), and 0.9% saline solution as a control (n = 7), respectively. Applications with 5 ml each were performed hourly within four hours. Lung function, haemodynamics, and pharmacokinetics were monitored. Bronchial lavage samples for captive bubble surfactometry and lung samples for histology and electron microscopy were removed. RESULTS: Arterial pressure of oxygen (PaO2) decreased significantly over the observation period of 4 hours in all animals. Compared to saline, 1% NCT + 1% NH4Cl led to significantly lower PaO2 values at the endpoint after 4 hours (62 +/- 9.6 mmHg vs. 76 +/- 9.2 mmHg, p = 0.014) with a corresponding increase in alveolo-arterial difference of oxygen partial pressure (AaDO2) (p = 0.004). Interestingly, AaDO2 was lowest with 1% NCT, even lower than with saline (p = 0.016). The increase of pulmonary artery pressure (PAP) over the observation period was smallest with 1% NCT without difference to controls (p = 0.91), and higher with 5% NCT (p = 0.02), and NCT + NH4Cl (p = 0.05).Histological and ultrastructural investigations revealed no differences between the test and control groups. The surfactant function remained intact. There was no systemic resorption of NCT detectable, and its local inactivation took place within 30 min. The concentration of NCT tolerated by A549 lung epithelial cells in vitro was similar to that known from other body cells (0.25-0.5 mM). CONCLUSION: The endogenous antiseptic NCT was well tolerated at a concentration of 1% upon inhalation in the pig model. Addition of ammonium chloride in high concentration provokes a statistically significant impact on blood oxygenation.

Ultraviolet A induces transport of compatible organic osmolytes in human dermal fibroblasts.

Compatible organic osmolytes, such as betaine, myo-inositol and taurine, are involved in cell protection. Human dermal fibroblasts accumulate these osmolytes and express mRNA specific for their transporting systems betaine-/gamma-amino-n-butyric acid (GABA) transporter (BGT-1), sodium-dependent myo-inositol transporter (SMIT) and taurine transporter (TAUT). Taurine uptake was about sixfold higher than that of betaine and myo-inositol. Compared with normoosmotic (305 mOsm/l) control, hyperosmotic exposure (405 mOsm/l) led to a twofold induction of osmolyte uptake. Ultraviolet A (UVA) upregulated osmolyte transporter mRNA levels and increased osmolyte uptake. Taurine inhibited UVA-induced interleukin-6 (Il-6) mRNA expression by 40%. Furthermore, Il-6 accumulation in the supernatants of UVA-irradiated dermal fibroblasts was much slower when cells were preincubated with taurine. These data indicate that taurine accumulation seems to be part of the fibroblast response to UVA radiation and may protect against UVA-induced Il-6 overexpression.

Thrombin increases hyposmotic taurine efflux and accelerates ICI-swell and RVD in 3T3 fibroblasts by a src-dependent EGFR transactivation.

The present study in Swiss3T3 fibroblasts examines the effect of thrombin on hyposmolarity-induced osmolyte fluxes and RVD, and the contribution of the src/EGFR pathway. Thrombin (5 U/ml) added to a 30% hyposmotic medium markedly increased hyposmotic 3H-taurine efflux (285%), accelerated the volume-sensitive Cl- current (ICI-swell) and increased RVD rate. These effects were reduced (50-65%) by preventing the thrombin-induced intracellular Ca2+ [Ca2+]i rise with EGTA-AM, or with the phospholipase C (PLC) blocker U73122. Ca2+calmodulin (CaM) and calmodulin kinase II (CaMKII) also participate in this Ca2+-dependent pathway. Thrombin plus hyposmolarity increased src and EGFR phosphorylation, whose blockade by PP2 and AG1478, decreased by 30-50%, respectively, the thrombin effects on hyposmotic taurine efflux, ICI-swell and RVD. Ca2+- and src/EGFR-mediated pathways operate independently as shown by (1) the persistence of src and EGFR activation when [Ca2+]i rise is prevented and (2) the additive effect on taurine efflux, ICI-swell or RVD by simultaneous inhibition of the two pathways, which essentially suppressed these events. PLC-Ca2+- and src/EGFR-signaling pathways operate in the hyposmotic condition and because thrombin per se failed to increase taurine efflux and ICI-swell under isosmotic condition it seems that it is merely amplifying these previously activated mechanisms. The study shows that thrombin potentiates hyposmolarity-induced osmolyte fluxes and RVD by increasing src/EGFR-dependent signaling, in addition to the Ca2+-dependent pathway.

Pharmacokinetics of taurolidine following repeated intravenous infusions measured by HPLC-ESI-MS/MS of the derivatives taurultame and taurinamide in glioblastoma patients.

BACKGROUND AND OBJECTIVE: Taurolidine is known to have antimicrobial activity. Furthermore, at lower concentrations, it has been found to exert a selective antineoplastic effect in vitro and in vivo. The aim of this study was to investigate the pharmacokinetics of taurolidine in vivo following repeated intravenous infusion in a schedule used for the treatment of glioblastoma. As a prerequisite, the pharmacokinetics of taurolidine in human blood plasma and whole blood in vitro was investigated. PATIENTS AND METHODS: The pharmacokinetics of taurolidine and its derivatives taurultame and taurinamide were investigated in human blood plasma and in whole blood in vitro using blood from a healthy male volunteer. During repeated intravenous infusion therapy with taurolidine, plasma samples were taken every hour for a period of 13 hours per day in seven patients (three male, four female; mean age 48.4 +/- 12.8 years, range 27-66 years) with a glioblastoma. Following dansyl derivatisation, the concentrations of taurultame and taurinamide were determined using a new method based on high-performance liquid chromatography (HPLC) online coupled to electrospray ionisation tandem mass spectrometry (ESI-MS/MS) in the multiple reaction monitoring mode. Under the experimental conditions used, taurolidine could not be determined directly and was back-calculated from the taurultame and taurinamide values. RESULTS: The new HPLC-ESI-MS/MS method demonstrated high accuracy and reproducibility. In vitro plasma concentrations of taurultame and taurinamide remained constant over the incubation period. In whole blood in vitro, a time-dependent formation of taurinamide was observed. At the start of the incubation, the taurultame-taurinamide ratio (TTR) was 0.95 at an initial taurolidine concentration of 50 microg/mL, and 1.69 at 100 microg/mL. The concentration of taurultame decreased at the same rate as the taurinamide concentration increased, showing logarithmic kinetics. The calculated taurolidine concentration remained largely constant over the 6-hour incubation period. During repeated infusions in patients, calculated plasma concentrations of taurolidine showed a strong increase after the start of each infusion and continued to increase until the end of infusion, followed by a rapid decline. The TTR was found to fluctuate between 0.1 and 0.3, depending on the relation to the previous or next infusion period. The volume of distribution was markedly higher for taurolidine, taurultame and taurinamide than the plasma volume. CONCLUSIONS: Taurolidine displayed a stable pattern of derivatives in plasma in vitro, whereas in whole blood, a time- and concentration-dependent conversion was apparent. In patients, the calculated average taurolidine plasma concentration, achieved with the repeated infusion regimen, was in the antineoplastic-effective concentration range. The tissue concentrations of taurolidine and taurultame are expected to be higher than the plasma concentrations, taking into account the calculated volumes of distribution. Repeated infusion of taurolidine is the therapeutically adequate mode of administration for the indication of glioblastoma.

The pharmacokinetics of taurolidine metabolites in healthy volunteers.

Taurolidine is an experimental antibacterial and antiendotoxic compound whose clinical utility as an antitumor agent is being investigated in human clinical trials. Taurolidine in aqueous solution exists in equilibrium with taurultam. Taurultam is subsequently transformed to taurinamide. The pharmacokinetic profiles of these metabolites are not well established. In this study, 18 healthy volunteers were administered 5.0 g of taurolidine in 250 mL of 5% polyvinylpyrrolidone in water over 2, 1, or 0.5 hours by intravenous infusion in a parallel-group design. All subjects noted discomfort at the infusion site, although there were no serious adverse events. t(max) generally occurred at the end of infusion for taurinamide, whereas that of taurultam was reached before completion of infusion. The taurolidine metabolite taurultam demonstrated a shorter half-life and lower systemic exposure than taurinamide. Shortening of infusion duration increased the C(max) and AUC of taurultam. Changes in infusion rate did not substantially change the pharmacokinetic parameters of taurinamide.

Targeting soluble Abeta peptide with Tramiprosate for the treatment of brain amyloidosis.

Amyloid beta-peptide (Abeta) is a major constituent of senile plaques in Alzheimer's disease (AD). Neurotoxicity results from the conformational transition of Abeta from random-coil to beta-sheet and its oligomerization. Among a series of ionic compounds able to interact with soluble Abeta, Tramiprosate (3-amino-1-propanesulfonic acid; 3APS; Alzhemedtrade mark) was found to maintain Abeta in a non-fibrillar form, to decrease Abeta(42)-induced cell death in neuronal cell cultures, and to inhibit amyloid deposition. Tramiprosate crosses the murine blood-brain barrier (BBB) to exert its activity. Treatment of TgCRND8 mice with Tramiprosate resulted in significant reduction (approximately 30%) in the brain amyloid plaque load and a significant decrease in the cerebral levels of soluble and insoluble Abeta(40) and Abeta(42) (approximately 20-30%). A dose-dependent reduction (up to 60%) of plasma Abeta levels was also observed, suggesting that Tramiprosate influences the central pool of Abeta, changing either its efflux or its metabolism in the brain. We propose that Tramiprosate, which targets soluble Abeta, represents a new and promising therapeutic class of drugs for the treatment of AD.

Aquaporin expression and cell volume regulation in the SV40 immortalized rat submandibular acinar cell line.

The amount of aquaporins present and the cellular ability to perform regulatory volume changes are likely to be important for fluid secretions from exocrine glands. In this work these phenomena were studied in an SV40 immortalized rat submandibular acinar cell line. The regulatory cell volume characteristics have not previously been determined in these cells. Cell volume regulation following hyposmotic exposure and aquaporin induction was examined with Coulter counter methodology, radioactive efflux studies, fura-2 fluorescence, and polymerase chain reaction and Western blot techniques. Cell volume regulation was inhibited by the K(+) channel antagonists quinine and BaCl(2) and the Cl(-) channel blocker 5-nitro-2-(3-phenypropylamino)benzoic acid. A concomitant increase in cellular (3)H-taurine release and Ca(2+) concentration was also observed. Chelation of both intra- and extracellular Ca(2+) with EGTA and the Ca(2+) ionophore A23187 did not, however, affect cell volume regulation. Aquaporin 5 (AQP5) mRNA and protein levels were upregulated in hyperosmotic conditions and downregulated upon return to isosmotic solutions, but were reduced by the mitogen-activated ERK-activating kinase (MEK) inhibitor U0126. A 24-h MEK inhibition also diminished hyposmotically induced cell swelling and cell volume regulation. In conclusion, it was determined that regulatory volume changes in this immortalized cell line are due to KCl and taurine efflux. In conditions that increased AQP5 levels, the cells showed a faster cell swelling and a more complete volume recovery following hyposmotic exposure. This response could be overturned by MEK inhibition.

Effects of consecutive high-dose alcohol administration on the utilization of sulfur-containing amino acids by rats.

In this study, we attempted to evaluate changes in sulfur-containing amino acid (SCAA) metabolism after short-term high-dose alcohol ingestion. At the beginning of the study, six animals were sacrificed as the baseline group and then other animals in the experiment were consecutively gavaged with alcohol (30%, 3 g/kg) for 7 days. Animals (n=6 each) were subsequently sacrificed at the time points of Days 1 (Group E1), 3 (Group E3) and 7 (Group E7). Blood samples and selected tissues were collected at each time interval. SCAA, pyridoxal phosphate (PLP) and glutathione (GSH) levels were analyzed. Results showed that taurine levels of tissues (brain, liver, heart and kidneys) all declined after the ethanol intervention and continued to decrease in selected tissues except the brain during the experiment. Furthermore, the trends of plasma taurine and PLP contents were highly correlated (r=.98, P=.045). A similar utilization pattern of plasma taurine and PLP indicated that transsulfuration preferred taurine production to GSH synthesis. The trend of plasma taurine levels being positively correlated with PLP levels reveals that dramatic transsulfuration occurred to meet the urgent demand for taurine by brain cells. In conclusion, we reported that continual alcohol ingestion alters SCAA utilization, especially by depletion of taurine and hypotaurine and by elevation of S-adenosyl homocysteine in the selected organs.

Taurine uptake by human retinal pigment epithelium: implications for the transport of small solutes between the choroid and the outer retina.

PURPOSE: To characterize the Michaelis-Menten kinetics of the taurine transporter (TT) in retinal pigment epithelium (RPE) freshly isolated from human donor eyes. To identify the rate limiting compartment in the pathway of taurine delivery from the choroidal blood supply to the outer retina composed by Bruch's-choroid (BC) and the RPE in the human older age group. METHODS: In human donor samples (4 melanoma-affected eyes, and 14 control eyes; age range, 62-93 years), radiochemical techniques were used to determine the RPE taurine accumulation at various exogenous concentrations. The transport capability of human RPE was obtained from a kinetic analysis of the high-affinity carrier over a substrate concentration of 1 to 60 microM taurine. RESULTS: Uptake of taurine into human RPE at a taurine concentration of 1 microM was independent of donor age (P > 0.05) and averaged at 2.83 +/- 0.27 (SEM) pmol/10 minutes per 6-mm trephine. Taurine transport by human RPE was mediated by a high-affinity carrier of K(m) 50 microM and V(max) of 267 pmol/10 minutes per 5-mm disc. CONCLUSIONS: In human donor RPE, uptake of taurine remained viable in the age range 62 to 93 years. Taurine transport rates in the RPE were lower than across the isolated BC complex, and thus the data suggest that the former compartment houses the rate-limiting step in the delivery of taurine to the outer retina.

Optimal and effective oral dose of taurine to prolong exercise performance in rat.

The aim of this study was to determine the effective and optimum dose of taurine for exercise performance and to maintain tissue taurine concentration. Rats received a respective daily dose of 0, 20, 100, and 500 mg/kg body weight of taurine (EC and ET-1, -2, -3 groups, respectively) for two weeks, and then, were subjected to treadmill until exhaustion. The running time to exhaustion was significantly prolonged by 25% and 50% in the ET-2 and -3 groups, respectively, compared to that in the EC group accompanied with maintenance of taurine tissue concentrations. Furthermore, the oxidative glutathione per total glutathione ratio in tissues was inhibited in the ET-2 and -3 groups whereas it was higher in the EC group than in both the no exercise and taurine-administered groups. Therefore the effective and optimal doses of oral taurine administration for two weeks on a transient exercise performance were between 100 and 500 mg/kg/day.

The osmolyte strategy of normal human keratinocytes in maintaining cell homeostasis.

Compatible organic osmolytes, such as betaine, myoinositol, and taurine, are involved in cell volume homeostasis as well as in cell protection, for example, against oxidative stress. This so-called osmolyte strategy requires the expression of specific osmolyte transporting systems such as the betaine/gamma-amino-n-butyric acid (GABA) transporter, the sodium-dependent myoinositol transporter and the taurine transporter (TAUT). In contrast to liver, kidney, and neural cells, nothing is known about osmolytes in the skin. Here we report that primary normal human keratinocytes (NHK) express mRNA specific for the betaine/GABA transporter, for the sodium-dependent myoinositol transporter and for the TAUT. In comparison to normoosmotic (305 mosmol per L) controls, a 3-5-fold induction of mRNA expression for the betaine/GABA-, the sodium-dependent myoinositol- and the TAUT was observed within 6-24 h after hyperosmotic exposure (405 mosmol per L). Expression of osmolyte transporters was associated with an increased uptake of radiolabeled osmolytes. Conversely, hypoosmotic (205 mosmol per L) stimulation induced significant efflux of these osmolytes. Exposure to ultraviolet B (290-315 nm) or ultraviolet A (340-400 nm) radiation, which are major sources of oxidative stress in skin, significantly stimulated osmolyte uptake. Increased osmolyte uptake was associated with upregulation of mRNA steady-state levels for osmolyte transporters in irradiated cells. These studies demonstrate that NHK possess an osmolyte strategy, which is important for their capacity to maintain cell volume homeostasis and seems to be part of their response to UV radiation.

Taurolidine-Fibrin-Sealant-Matrix using spray application for local treatment of brain tumors.

Malignant gliomas tend to recur in the vast majority of cases. Recurrent gliomas may arise from vital tumor cells present in this zone around the resection margin. It appears promising to combine tumor resection with local chemotherapy using an antineoplastic, but non-toxic agent. Taurolidine exerts a selective antineoplastic effect by induction of programmed cell death and has anti-angiogenic activity. Fibrin sealant is completely degradable and firmly adheres to brain tissue, suggesting that it would provide a suitable matrix for taurolidine delivery--a Taurolidine-Fibrin-Sealant-Matrix (TFM)--in the local treatment of brain tumors. The potential of local delivery of taurolidine out of a fibrin sealant matrix was investigated. Taurolidine could be suspended homogeneously in both the thrombin and the procoagulant protein components of the fibrin sealant. The fibrin sealant matrix was a suitable carrier for the suspension of taurolidine at a concentration that ensured the release of therapeutically effective amounts of the drug over a period of 2 weeks in vitro. The antineoplastic action of taurolidine was not affected by embedding in the fibrin sealant matrix. The described drug delivery system may be suitable for local taurolidine treatment of brain tumors following complete or partial resection or of tumors that are non-resectable because of their location.